Abstract
Vasohibin-1 (VASH1) is a VEGF-inducible endothelium-derived angiogenesis inhibitor and VASH2 is its homolog. Our previous analysis revealed that VASH1 is expressed in endothelial cells to terminate angiogenesis, whereas VASH2 is expressed in infiltrating mononuclear cells mobilized from bone marrow to promote angiogenesis in a mouse model of hypoxia-induced subcutaneous angiogenesis. To test the possible involvement of VASH2 in the tumor, we examined human ovarian cancer cells for the presence of VASH2. Immunohistochemical analysis revealed that VASH2 protein was preferentially detected in cancer cells of serous ovarian adenocarcinoma. We then used SKOV-3 and DISS, two representative human serous adenocarcinoma cell lines, and examined the role of VASH2 in the tumor. The knockdown of VASH2 showed little effect on the proliferation of cancer cells in vitro but notably inhibited tumor growth, peritoneal dissemination, and tumor angiogenesis in a murine xenograft model. Next, we stably transfected the human VASH2 gene into two types of murine tumor cells, EL-4 and MLTC-1, in which endogenous VASH2 was absent. When either EL-4 or MLTC-1 cells were inoculated into VASH2 (-/-) mice, the VASH2 transfectants formed bigger tumors when compared with the controls, and the tumor microvessel density was significantly increased. VASH2 stimulated the migration of endothelial cells, and its increased expression in cancer cells is related to the decrease of mir-200b. These results indicate that VASH2 expressed in serous ovarian carcinoma cells promoted tumor growth and peritoneal dissemination by promoting angiogenesis.
Highlights
Ovarian cancer is the second most common malignant tumor in gynecology and is the leading cause of cancerrelated death for women worldwide [1]
Our analysis revealed that VASH1 is mainly expressed in endothelial cells in the termination zone to halt angiogenesis, whereas VASH2 is mainly expressed in mononuclear cells mobilized from the bone marrow in the sprouting front to stimulate angiogenesis [16]
VASH2 is expressed in human serous ovarian carcinoma cells
Summary
Ovarian cancer is the second most common malignant tumor in gynecology and is the leading cause of cancerrelated death for women worldwide [1]. It is critical to develop alternative options that target pathways responsible for the progression of ovarian cancer. Angiogenesis is recognized as one of the principal hallmarks of various cancers [3]. Tumor angiogenesis is thought to be a Authors' Affiliations: 1Department of Vascular Biology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai; 2Department of Obstetrics and Gynecology, School of Medicine, Jichi Medical University, Tochigi; and 3Department of Pathology 2, Kawasaki Medical University, Kurashiki, Japan. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).
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